Leaflet IMDYLLTRA 10mg powder for concentrate and solution for infusion

IMDYLLTRA treatment should be initiated under the direction of and supervised by physiciansexperienced in the use of cancer therapy. It should be administered in an appropriate healthcarefacility. See table 2 for recommended concomitant medicinal products.

Patients should be monitored from the start of the infusion for 6 to 8 hours on day 1 and day 8.

Additional monitoring and monitoring on subsequent infusions is at the discretion of the physician.

On day 1 and day 8, patients should be instructed to remain within proximity of an appropriatehealthcare facility for 24 hours starting from each infusion, accompanied by a caregiver.

Both patients and caregivers should be informed on signs and symptoms of cytokine release syndrome(CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) prior to discharge.

The recommended dosing schedule of IMDYLLTRA is an initial dose of 1 mg on day 1 followed by10 mg on days 8, 15, and every 2 weeks thereafter as shown in table 1.

Patients should be treated until disease progression or unacceptable toxicity.

Table 1. Recommended dosing schedule of IMDYLLTRA

Dose of IMDYLLTRA

Day 1 1 mg

Day 8 10 mg

Day 15 and every 2 weeks10 mgthereafter

Recommended concomitant medicinal products

Concomitant medicinal products for IMDYLLTRA administration should be administered aspresented in table 2 to reduce the risk of cytokine release syndrome (see section 4.4).

Table 2. Concomitant medicinal products for day 1 and day 8

Treatment day Medicinal products Administration

Day 1 and day 8 Administer 8 mg of dexamethasone Within 1 hour prior to IMDYLLTRAintravenously (or equivalent) infusion

Intravenous administration of 1 litre Immediately after completion ofof sodium chloride 9 mg/mL (0.9%) IMDYLLTRA infusionsolution for injection is recommendedper standard of care guidelines

Restarting IMDYLLTRA after dose delay

If a dose of IMDYLLTRA is delayed, therapy should be restarted based on the recommendationslisted in table 3, and the dosing schedule should be resumed accordingly. Recommended concomitantmedicinal products should be administered as indicated in table 2.

Table 3. Recommendations for restarting therapy with IMDYLLTRA after dose delay

Last dose Time since the last dose Actionaadministered administered2 weeks or less Administer IMDYLLTRA 10 mg, then resume(≤ 14 days) with the planned dosing schedule.

1 mg on day 1 Administer IMDYLLTRA 1 mg. If tolerated,

Greater than 2 weeksincrease to 10 mg 1 week later. Then resume with(> 14 days)the planned dosing schedule.

Last dose Time since the last dose Actionaadministered administered3 weeks or less Administer IMDYLLTRA 10 mg, then resume(≤ 21 days) with the planned dosing schedule.

10 mg on day 8 Administer IMDYLLTRA 1 mg. If tolerated,

Greater than 3 weeksincrease to 10 mg 1 week later. Then resume with(> 21 days)the planned dosing schedule.

4 weeks or less Administer IMDYLLTRA 10 mg, then resume10 mg on day 15 (≤ 28 days) with the planned dosing schedule.

and every 2 weeks Administer IMDYLLTRA 1 mg. If tolerated,

Greater than 4 weeksthereafter increase to 10 mg 1 week later. Then resume with(> 28 days)the planned dosing schedule.

a Administer recommended concomitant medicinal products before and after IMDYLLTRA infusions on day 1and day 8 and monitor patients accordingly (see table 2).

Dose modifications and management of adverse reactions

No dose reduction for IMDYLLTRA is recommended.

See table 4 for recommended actions for the management of CRS, table 5 for recommended actionsfor the management of ICANS, and table 6 for the management of other adverse reactions.

CRS should be diagnosed based on clinical presentation (see section 4.4). Patients should be evaluatedand treated for other causes of fever, hypoxia, and hypotension. If CRS is suspected, it should bemanaged according to the recommendations in table 4. Patients who experience grade 2 or higher CRS(e.g., hypotension not responsive to fluids, or hypoxia requiring supplemental oxygen) should bemonitored for CRS signs and symptoms including fever, hypotension and hypoxia using pulseoximetry or cardiac telemetry as indicated. For severe or life-threatening CRS, anti-IL-6 therapy isrecommended, for example, tocilizumab and admission in an intensive-care unit (ICU) for supportivetherapy.

Table 4. Guidelines for grading, dose modification and management of cytokine releasesyndromea

CRS IMDYLLTRA

Defining symptoms Managementgrade dose modification

Grade 1 Symptoms require * Withhold * Administer symptomaticsymptomatic treatment IMDYLLTRA until antipyretic treatmentonly (e.g., fever ≥ 38°C event resolves, then (e.g., paracetamol) forwithout hypotension or resume IMDYLLTRA fever.hypoxia). at the next scheduled * Considerdoseb. dexamethasonec (orequivalent) 4 mg to10 mg orally orintravenously.

CRS IMDYLLTRA

Defining symptoms Managementgrade dose modification

Grade 2 Symptoms require and * Withhold * Hospitalisation withrespond to moderate IMDYLLTRA until monitoring for fever,intervention. event resolves, then hypotension and hypoxia

* Fever ≥ 38°C, resume IMDYLLTRA using pulse oximetry or,

* Hypotension at the next scheduled as indicated, cardiacresponsive to doseb. telemetry, isfluids not recommended.

requiring * Administer symptomaticvasopressors, antipyretic treatmentand/or (e.g., paracetamol) for

* Hypoxia fever.

requiring low * Administer supplementalflow nasal oxygen and intravenouscannula or fluids when indicated.

blow-by. * Considerdexamethasonec (orequivalent) 8 mg orallyor intravenously.

* Consider tocilizumab (orequivalent).

When resuming treatment atthe next planned dose, monitorpatients at the physician’sdiscretion in an appropriatehealthcare facilityb.

Grade 3 Severe symptoms * Withhold In addition to grade 2defined as temperature IMDYLLTRA until treatment:

≥ 38°C with: the event resolves, * Intensive monitoring,

* Haemodynamic then resume e.g., ICU care isinstability IMDYLLTRA at the recommended.

requiring a next scheduled doseb. * Administervasopressor (with * For recurrent grade 3 dexamethasonec (oror without events, permanently equivalent) 8 mgvasopressin) discontinue intravenously everyand/or IMDYLLTRA. 8 hours up to 3 doses.

* Worsening * Vasopressor support ashypoxia or needed.respiratory * High flow oxygendistress requiring support as needed.high flow nasal * Tocilizumab (orcanula (> 6 L/min equivalent) isoxygen) or face recommended.mask. * Prior to the next dose,administer concomitantmedicinal products asrecommended for day 1and day 8 (see table 2).

When resuming treatment atthe next planned dose, monitorpatients at the physician’sdiscretion in an appropriatehealthcare facilityb.

CRS IMDYLLTRA

Defining symptoms Managementgrade dose modification

Grade 4 Life-threatening Permanently discontinue * ICU care.symptoms defined as IMDYLLTRA. * Per grade 3 treatment.temperature ≥ 38°C

with:

* Haemodynamicinstabilityrequiring multiplevasopressors(excludingvasopressin)and/or

* Worseninghypoxia orrespiratorydistress despiteoxygenadministrationrequiring positivepressure.a CRS based on American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading(2019).b See table 3 for recommendations on restarting IMDYLLTRA after dose delays.c Taper steroids per standard of care guidelines.

ICU = Intensive Care Unit

Immune effector cell-associated neurotoxicity syndrome (ICANS)

Patients should be monitored for signs and symptoms of ICANS. Other causes of neurologicsymptoms should be ruled out. Intensive care should be provided for severe or life-threateningneurologic toxicities. If ICANS is suspected, it should be managed according to the recommendationsin table 5.

Table 5. Guidelines for grading, dose modification and management of immune effectorcell-associated neurotoxicity syndromea

ICANS Defining IMDYLLTRA dosea Managementgrade symptoms modification

Grade 1 ICE score 7-9b * Withhold IMDYLLTRA * Supportive care.with no until ICANS resolves,depressed level then resumeof consciousness. IMDYLLTRA at thenext scheduled dosec.

ICANS Defining IMDYLLTRA dosea Managementgrade symptoms modification

Grade 2 ICE score 3-6b * Withhold IMDYLLTRA * Supportive care.and/or mild until ICANS resolves, * Dexamethasoned (orsomnolence then resume equivalent) 8 mg to 10 mgawaking to IMDYLLTRA at the orally or intravenously.voice. next scheduled dosec. * If symptoms worsen, repeatdexamethasone every12 hours ormethylprednisoloned (orequivalent) 1 mg/kgintravenously every12 hours.

* Monitor neurologicsymptoms and considerconsultation withneurologist and otherspecialists for furtherevaluation and management.

* Monitor patients at thephysician’s discretionfollowing the next dose of

IMDYLLTRAc.

Grade 3 ICE score 0-2b * Withhold IMDYLLTRA * Intensive monitoring, e.g.,and/or depressed until the ICANS ICU care is recommended.level of resolves, then resume * Consider mechanicalconsciousness IMDYLLTRA at the ventilation for airwayawakening only next scheduled dosec. protection. Dexamethasonedto tactile * If there is no (or equivalent) 10 mgstimulus and/or improvement to intravenously every 6 hoursany clinical grade ≤ 1 within 7 days, or methylprednisoloned (orseizure focal or permanently discontinue equivalent) 1 mg/kggeneralised that IMDYLLTRA. intravenously everyresolves rapidly * For recurrent grade 3 12 hours.events, permanently * Consider repeat

Or discontinue. neuroimaging (CT or MRI)every 2-3 days if patient has

Nonconvulsive persistent grade ≥ 3seizures on EEG neurotoxicity.that resolve with * Monitor patients at theintervention physician’s discretionand/or focal or following the next dose oflocal oedema IMDYLLTRAc.seen onneuroimaging.

ICANS Defining IMDYLLTRA dosea Managementgrade symptoms modification

Grade 4 ICE score 0b * Permanently discontinue * ICU care.(patient is IMDYLLTRA. * Consider mechanicalunarousable and ventilation for airwayunable to protection.perform ICE) * High-dose corticosteroidsand/or stupor or such as methylprednisolonedcoma and/or 1 000 mg/day in dividedlife-threatening doses intravenously forprolonged 3 days.seizure * Consider repeat(> 5 minutes) or neuroimaging (CT or MRI)repetitive clinical every 2-3 days if patient hasor electrical persistent grade ≥ 3seizures without neurotoxicity.return to baseline * Treat convulsive statusin between epilepticus per institutionaland/or diffuse guidelines.cerebral oedemaonneuroimaging,decerebrate ordecorticateposturing orpapilloedema,cranial nerve VIpalsy, or

Cushing’s triad.a ICANS based on American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading(2019).b If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE)

Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (names 3 objects,e.g., point to clock, pen, button = 3 points); Following commands (e.g., “show me 2 fingers” or “close your eyesand stick out your tongue” = 1 point); Writing (ability to write a standard sentence = 1 point); and Attention(count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment(grade 4 ICANS) = 0 points.c See table 3 for recommendations on restarting IMDYLLTRA after dose delays.d Taper steroids per standard of care guidelines.

CT = Computed Tomography; EEG = Electroencephalogram; ICU = Intensive Care Unit; MRI = Magneticresonance imaging

Neutropenia and other adverse reactions

Neutropenia and other adverse reactions should be managed in accordance with table 6.

Table 6. Recommended treatment interruptions of IMDYLLTRA for the management of otheradverse reactionsa,b

Adverse

Severitya Dose modificationbreactions

Neutropenia Grades 1 and 2 No treatment interruption needed.

(see section 4.4) * Interrupt IMDYLLTRA for atleast 3 days and until the eventimproves to grade ≤ 2, then

Grade 3resume IMDYLLTRA.

Consider using granulocyte-colonystimulating factor (G-CSF).

* Interrupt IMDYLLTRA for atleast 3 days and until the eventimproves to grade ≤ 2, thenresume IMDYLLTRA.

* If event lasts for > 7 days or

Grade 4grade 4 event reoccurs,permanently discontinue

IMDYLLTRA.

Consider using granulocyte-colonystimulating factor (G-CSF).

Hepatotoxicity Grade 3 * Withhold IMDYLLTRA until(see section 4.4)c Increased ALT or AST or bilirubin improved to grade ≤ 1.

Grade 4 * Permanently discontinue

Increased ALT or AST or bilirubin IMDYLLTRA.

AST or ALT > 3 × ULN with total * Permanently discontinuebilirubin> 2 × ULN in the absence of IMDYLLTRA.alternative causes

Other adverse Withhold IMDYLLTRA untilreactions (see recovery to grade ≤ 1 or baseline.

section 4.8)

Consider permanently discontinuingif adverse reaction does not resolve

Grade 3 or 4within 28 days.

* Consider permanentdiscontinuation for grade 4events.a Severity based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE),

Version 5.0.b See table 3 for recommendations on restarting IMDYLLTRA after dose delays.c For patients with liver enzyme elevations at baseline, multiples of baseline values should be used forhepatotoxicity assessment.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal

No dose adjustment is necessary in elderly patients (≥ 65 years of age).

No dose adjustment is required in patients with mild hepatic impairment (see section 5.2). Limiteddata is available in patients with moderate hepatic impairment. IMDYLLTRA has not been studied inpatients with severe hepatic impairment. No dose recommendations can be made for patients withmoderate or severe hepatic impairment.

No dose adjustment is required in patients with mild or moderate renal impairment (see section 5.2).

IMDYLLTRA has not been studied in patients with severe renal impairment. No doserecommendations can be made for patients with severe renal impairment to end-stage renal disease.

There is no relevant use of IMDYLLTRA in the paediatric population for the treatment of small celllung cancer.

IMDYLLTRA is for intravenous use.

IMDYLLTRA is to be reconstituted and then further diluted prior to administration by intravenousinfusion.

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 6.6.

The infusion line for premedication can be used for IMDYLLTRA. An infusion line flush should beconducted between administering concomitant medicinal products and IMDYLLTRA.

Administer the entire contents of IMDYLLTRA as an intravenous infusion over 1 hour at a constantflow rate using an infusion pump, see table 7. The pump should be programmable, lockable,non-elastomeric, and have an alarm.

The infusion line is primed with sodium chloride 9 mg/mL (0.9%) solution for injection OR finalprepared IMDYLLTRA.

Upon completion of the IMDYLLTRA infusion, the intravenous infusion line should be flushed over3-5 minutes using sodium chloride 9 mg/mL (0.9%) solution for injection.

Table 7. Tarlatamab administration information

Infusion duration for 250 mL intravenous

Infusion rate (mL/hour)preparation1 hour 250 mL/hour